Dextromethorphan metabolism in Jordanians: dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation.

The concentrations of dextromethorphan (DM) and its metabolites dextrorphan (DRP), 3-methoxymorphinan (MM) and 3-hydroxymorphinan (HM) were measured in 8 h urine samples from 266 unrelated healthy Jordanian subjects following oral administration of 30 mg dextromethorphan hydrobromide and using a rapid, sensitive and precise HPLC method with fluorometric detection. The frequency of the 'poor' metabolizer status of DM-O-demethylation as judged by log DM/DRP was found to be 6.8% with a 95% confidence interval of 3.8-9.8%. There was a strong correlation between log DM/DRP and log total non-O-demethylated compounds (NODM)/total O-demethylated metabolites (ODM) metabolic ratios (r = 0.96, P < 0.01). However, one subject with log DM/DRP of 0.05 that classifies him as a poor metabolizer was found to have a log NODM/ODM of -0.73 which is in the range of extensive metabolizer status suggesting the presence of another cytochrome P450 isoenzyme involved in dextromethorphan O-demethylation. Dextromethorphan N-demethylation to 3-methoxymorphinan was detected in 55.3% of individuals. Furthermore, a dissociation between dextromethorphan O-demethylation and debrisoquine (D) 4-hydroxylation has been observed. Among the 116 subjects phenotyped with both dextromethorphan and debrisoquine, 7 were poor metabolizers of both, three were poor metabolizers of debrisoquine and extensive metabolizers of dextromethorphan whilst 4 were poor metabolizers of dextromethorphan and extensive metabolizers of debrisoquine, one of whom was reclassified as an extensive metabolizer of dextromethorphan using log NODM/ODM to characterize dextromethorphan metabolizer status.

Metoprolol alpha-hydroxylation is a poor probe for debrizoquine oxidation (CYP2D6) polymorphism in Jordanians.

The frequency distribution of the 8-h urinary ratio of log metoprolol/alpha-hydroxymetoprolol was assessed in 65 healthy, unrelated Jordanian volunteers. There was no apparent bimodality in the frequency distribution of this ratio among the subjects studied. The frequency of the poor metabolizer phenotype of metoprolol alpha-hydroxylation was 1.5% (one subject). There was a significant correlation (r = 0.61, P < 0.05, n = 39) between the log metoprolol/alpha-hydroxymetoprolol and the log debrisoquine/4-hydroxydebrisoquine ratios. However, the frequency of poor metabolizer status of debrisoquine among the 39 subjects was 7.7% (three subjects). Only one of the poor metabolizer of metoprolol alpha-hydroxylation. These findings indicate that metoprolol alpha-hydroxylation by CYP2D6 represents a poor probe for studying debrisoquine polymorphism in Jordanians.

Gastrointestinal dialysis of digoxin using cholestyramine.

The pharmacokinetic parameters of digoxin given intravenously (0.075 mg/kg) alone and following treatment with oral cholestyramine (8 gm in 50 ml water) were studied in rabbits. Pretreatment with cholestyramine produced a significant decrease in the serum concentration of digoxin and significantly enhances its systemic clearance as indicated by a statistically significant decrease in the area under the concentration-time curve (AUC), half time of elimination (t 1/2), and mean residence time (MRT). These findings indicate that the idea of gastrointestinal dialysis, known with activated charcoal, could be extended to ion-exchange resins that could be a potentially useful adjunctive measure in the management of drug overdose especially with commonly used drugs with a low therapeutic index like digoxin.

Acetylation of dapsone by human whole blood.

We studied the acetylation of dapsone (DDS) in vitro by whole blood taken from subjects with known acetylator phenotype. The acetylation of DDS by whole blood was both incubation time- and DDS concentration-dependent. Thus, it is highly recommended to separate plasma immediately after blood withdrawal during acetylation phenotyping using DDS. para-aminobenzoic acid (PABA) substantially inhibited the acetylation of DDS by whole blood taken from both slow and rapid acetylators, while procainamide (PAD) significantly inhibited DDS acetylation by whole blood taken from slow acetylators. At the highest PAD concentration used (208 microM), DDS acetylation by whole blood taken from rapid acetylators was also inhibited. In contrast, sulphanilamide (SAD) failed to produce any significant inhibition of the acetylation of DDS by whole blood taken from either slow or rapid acetylators. Furthermore, there was no correlation between DDS acetylation by whole blood in vitro and the acetylator status of the subject. It is therefore not possible to predict the acetylator phenotype by studying DDS acetylation by human whole blood. These results indicate that the DDS N-acetyltransferase of human whole blood is most probably of the monomorphic type.

Dextromethorphan O-demethylation polymorphism in Jordanians.

The O-demethylation of dextromethorphan (DMT) to dextrorphan (DRP) was studied in 241 unrelated, healthy Jordanian volunteers (171 males, 70 females). Urine was collected for 8 h following a single oral dose of DMT bromhydrate 30 mg. A thin-layer chromatographic (TLC) technique was used to identify the metaboliser phenotype. The frequency of the poor metaboliser phenotype was found to be 2.9% (approximate 95% confidence interval 0.8-5.0%). Applying the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling poor metabolism was 0.17 (95% confidence interval 0.108-0.232).

Acetylator phenotypes of Jordanian diabetics.

The acetylator phenotype was determined in 31 insulin-dependent (IDDM) and 110 noninsulin-dependent (NIDDM) Jordanian diabetics, and was compared to that of 160 healthy volunteers of the same ethnic group. Dapsone was used as the test drug. The rapid acetylator phenotype was slightly less frequent in IDDM and slightly more frequent in NIDDM. Neither of the differences was significant. When acetylator status in the two types of diabetes mellitus was compared, there was a significant difference among the two groups. Patients with IDDM had a higher percentage of the slow acetylator phenotype when compared to NIDDM patients. The association between acetylator status and IDDM in Jordanians, which agrees with that reported for the Saudi Arabian population, is the reverse of what is found in European populations. The results demonstrate ethnic differences in acetylator status among IDDM patients.

N-acetylation phenotyping using dapsone in a Jordanian population.

1. The N-acetylation of dapsone (DDS) was studied in 160 unrelated healthy Jordanian volunteers. 2. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS), was 67.5% with a 95% confidence interval of 59 to 76%. Slow acetylators had an acetylation ratio of less than 0.42. 3. Applying the Hardy-Weinberg Law, the frequency of the recessive allele controlling slow acetylation was found to be 0.82 +/- 0.02. 4. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. The number of homozygous (n = 16) and heterozygous (n = 36) rapid acetylators derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 5 and n = 47) according to the Hardy-Weinberg Law. The suggested antimode used to discriminate the two groups was 0.82. 5. The mean plasma concentration of MADDS and the mean plasma acetylation ratio were about three times lower in slow than in rapid acetylators. However, there was no difference in mean plasma DDS concentration between slow and rapid acetylators. 6. There was a significant correlation (r = 0.853, P less than 0.001) between plasma MADDS concentration and the acetylation ratio. For DDS such a correlation was absent (r = 0.059, P = 0.23).

Simultaneous high performance liquid chromatographic determination of dapsone and monoacetyldapsone in human plasma and urine.

A rapid, specific and a one-stage protein precipitation method for simultaneous estimation of dapsone (DDS) and monoacetyldapsone (MAD) concentration in plasma and urine using high performance liquid chromatography (HPLC) is described. The applicability of the method for monitoring DDS and MAD blood levels in two different acetylator phenotype volunteers following the administration of 100-mg oral dose of DDS was shown. Cumulative urinary excretion of DDS and MAD were studied in the same volunteers.